This invention relates to a new ethanolate of azithromycin, processes for its manufacture, and pharmaceutical compositions containing the new ethanolate.
Azithromycin, 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, having the formula 
is a semi-synthetic macrolide antibiotic related to erythromycin A, useful for treating infections caused by susceptible microorganisms. This invention provides a new non-hygroscopic form of azithromycin, processes for its manufacture, and pharmaceutical compositions containing it.
Azithromycin may be made by methods described in U.S. Pat. Nos. 4,517,359 and 4,474,768. According to European Patent Application EP 298,650, the azithromycin obtained by these methods is a hygroscopic monohydrate. Because of its hygroscopic nature, this monohydrate is difficult to prepare and maintain in a form having a constant, reproducible water-content, and is particularly difficult to handle during formulation. EP 298,650 describes a dehydrate form of azithromycin that is less hygroscopic than the previously known monohydrate. The method described in EP 298,650 for making the dehydrate form is by crystallization from tetrahydrofuran, hexane and water.
Chinese Patent Application CN 1,093,370, describes an azithromycin crystal having water content of 4-6%. This form of azithromycin is stated as being less hygroscopic than the dehydrate described in EP 298,650. The method disclosed in CN 1,093,370 for making the described form of azithromycin is by crystallization from acetone and water.
The present invention provides a new ethanolate of azithromycin that is less hygroscopic than azithromycin monohydrate. The new ethanolate has an ethanol content of about 1.5% to about 3% and a water content of about 2% to about 4%.
The present invention also provides a method of making an ethanolate of azithromycin, comprising the steps of:
dissolving azithromycin in ethanol,
adding water to the azithromycin solution such that crystallization of the azithromycin begins and a suspension is formed, and
isolating the crystals of azithromycin.
The present invention further provides a pharmaceutical composition comprising a therapeutic amount of an ethanolate of azithromycin in accordance with the present invention and a pharmaceutically acceptable carrier.